FAMOTIDINE MICROSPHERES

1. ResearchArticle
PREPARATION AND CHARACTERIZATION OF FAMOTIDINE
MICROCAPSULE
EMPLOYING MUCOADHESIVE POLYMERS IN COMBINATION TO
ENHANCE
GASTRO RETENTION FOR ORALDELIVERY
BHABANI S NAYAK *1, SUNIL K GHOSH 1 AND K. TRIPATIB PATRO 2
1Jeypore College of Pharmacy, Faculty of Pharmacy, Rondapalli, Jeypore-764002,
Koraput, Orissa, India.2College of Pharmaceutical Sciences,
Mohuda, Berhampur – 760002, Ganjam, Orissa, India
E.mil: bhabani143@yahoo.co.in, Cell No: +919938860284 (M), Fax no- 06854-
246955.
Received – 28th May, 2009, Revised and Accepted – 20th July 2009
ABSTRACT:
A new sustained release microencapsulated drug delivery system
employing sustained release polymers in
combination has been proposed in this present study. The microcapsules
were formulated by orifice ionic gelation technique using
famotidine as the model drug and polymers combination forms like
(carbopol-934 and hydroxy
propyl methyl cellulose, carbopol-934 and sodium carboxy methyl
cellulose, carbopol-934 and methyl cellulose,
carbopol-934 and guar gum) against carbopol-934 only. Microcapsules
were evaluated for particle size, percentage
yield, flow properties, drug entrapment efficiency, surface morphology
by scanning electron microscopy (SEM),
sphericity measurement, percentage moisture loss, wall thickness,
swelling property, in vitro drug release profile,
drug release kinetic study and mucoadhesion study by in vitro wash off
test. The effect of drug and different
polymer combination on in vitro drug release profile was examined. The
famotidine microcapsules with good
structure and satisfactory yield were produced. Microcapsules
employing sustained release polymers used in

2. combination, exhibited slow release of famotidine over 9 hours with
zero order release kinetic fashion. It was
concluded that the polymer possess substantial release controlling
properties used in combination that could be used
for sustained drug delivery. All data were verified statistically by
employing one way ANOVA and found to be
significant at 5 % level of significance.
Keyword : Famotidine, Microencapsulation, Mucoadhesion
INTRODUCTION
Sustained release (SR) drug delivery system significantly improve
therapeutic efficacy of a drug. Drug release retarding polymers are
the key performer in such systems. Much of the development in SR drug
delivery systems Is focusing in the preparation and use of
polymers with specificity designed macroscopic and microscopic
structural and chemical features. Number of natural, semi
synthetic and synthetic polymer materials are used in the controlled
delivery of drugs. Recent trend towards the use of vegetable and
Non toxic products demands the replacement of synthetic additives with
natural one. The
Natural materials have been extensively used in the field of drug
delivery for their easy availability, cost effectiveness, Eco friendliness,
capable of multitude of chemical modifications, potentially degradable
and compatible due to natural origin. Past research therefore studied and
acknowledged.
various natural gum like agar, guar gum,chitosan, xanthium,
sodium alginate and lotus bean gum etc. for potential
pharmaceutical
and biomedical application.
The development of efficient orally delivered mucoadhesive
drug delivery system includes advantages
like, enhanced bioavailability, targeted
specific delivery to specific region of the GI
tract, maximized absorption rate due to
Intimate contact with the absorbing

3. membrane, improved drug protection by
polymer encapsulation and longer gut transit
time resulting in extended periods for
absorption.
Famotidine, a potent H2-receoter
antagonist was widely used in the treatment
of peptic ulcer in a dose of 20 mg b.i.d
associated with adverse effects like diarrhoea,
dizziness, headache and anorexia etc. The
plasma half life of drug was 2.5-3 hour as
reported in literature, which may exhibits
toxic effect in prolong use. Hence an attempt
was made in this current study to evaluate the
efficacy of combine polymers in designing of
sustained release mucoadhesive famotidine
microcapsule for oral delivery.
MATERIALS AND METHODS
Materials
Famotidine was received as a gift sample
from Nicholas Piramol India limited,
Mumbai. Carbopol-934, Sodium
carboxy methyl cellulose (SCMC), hydroxyl
propyl methyl cellulose (HPMC), methyl
cellulose and guar gum . All other chemical
and reagents used in this study were of
analytical grade and procured from
authorized dealer.
Preparation of microcapsules:
Mucoadhesive microcapsule were prepared
by orifice ionic gelation method with
polymers combinations such as carbopol
and HPMC, carbopol and SCMC, carbopol
and methyl cellulose, carbopol and guar
gum, against carbopol only, in the drug polymer
ratio of 1:3 w/w using famotidine

4. as model drug. Famotidine loaded
microcapsule were prepared by ionic
gelation method. Briefly 200 mg of sodium
alginate, 100 mg of polymer (First
carbopol-934 alone and then carbopol-934
with other polymers in ratio of 1:1 w/w) and
100 mg of drug were dispersed in 10 ml
water with a constant stirring at 300 rpm for
30 min. The resultant dispersion was added
drop wise through a syringe (17 gages) into
the CaCl2 solution (10 % w/v). The so
formed microcapsules (1:3 w/w ratio) were
kept for 30 min for complete reaction and
afterwards, microcapsule were recovered by
filtration through a sintered glass filter,
under vacuum, dried in hot air oven at 60°C
for 1 hour.
Percentage Yield:
The microcapsules were evaluated for
percentage yield and percent drug
entrapment. The yield was calculated as per
the equation,
Percentage yield = Weight of microcapsule recovered X 100
Weight (drug + polymer)
Particle size measurement:
The size of the prepared microcapsules was
measured by the optical microscopy method
using a calibrated stage micrometer. Particle
size was calculated by using equation,
Xg = 10 x [(ni x log Xi) / N], Where, Xg is
geometric mean diameter, ni is number of
particle in range, Xi is the mid point of
range and N is the total number of particles.
All the experimental units were analyzed in
triplicate (n=3).

5. Flow properties of microcapsules:
Flowability of microcapsules was
investigated by determining Angle of
repose, bulk density, Carr’s index and
Hausner ratio. The angle of repose was
determined by fixed funnel method. The
microcapsules were tapped using bulk
density apparatus (Excel Enterprises,
Kolkata) for 1000 taps in a cylinder and the
change in volume were measured. Carr
index and Hausner ratio were calculated by
the formula,
114
Carr index (%) = (Df-D0) ×100 ⁄ Df and
Hausner ratio = Df ⁄ D0, where, Df is poured
density; D0 is tapped density.
Drug entrapment efficiency (DEE):
Drug loaded microcapsules (100 mg) were
powdered and suspended in 100 ml water
solvent system. The resultant dispersion was
kept for 30 min for complete mixing with
continuous agitation and filtered through a
0.45 μm membrane filter. The drug content
was determined spectrophotometrically
(UV-Visible-1700, Shimadzu, Japan
spectrophotometer) at 265 nm using a
regression equation derived from the standard
graph (r2 = 0.9978). The drug entrapment
efficiency (DEE) was calculated by the
equation, DEE = (Pc / Tc) X 100, Where, Pc is
practical content, Tc is the theoretical content.
All the formulations were analyzed in
triplicate (n=3).
Scanning Electron Microscopy: (SEM)

6. The SEM analysis was carried out using a
scanning electron microscope (LEO, 435 VP,
U.K.). Prior to examination, samples were
mounted on an aluminium stub using a
double sided adhesive tape and making it
electrically conductive by coating with a thin
layer of gold (approximately 20 nm) in
vacuum. The scanning electron microscope
was operated at an acceleration voltage of 5
kV and resolution of 4000.
Percentage moisture loss:
The famotidine loaded microcapsules was
evaluated for percentage moisture loss which
sharing an idea about its hydrophilic nature.
The microcapsules weighed (W1) initially
kept in desiccator containing calcium chloride
at 37°C for 24 hours. The final weight (W2)
was noted when no further change in weight
of sample was observed.
Moisture loss = [(W1 – W2)/ W2] X 100. All
the experimental units were studied in
triplicate (n=3).
Determination of sphericity:
The particle shape was measure by computing
circulatory factor (S). The tracing obtained
from optical microscopy were used to
calculate Area (A) and perimeter (P).
This will indicate the approximate shape of
the prepared microcapsule calculated by the
equation, S = P2/ 12.56 × A. All the
experimental units were studied in
triplicate (n=3).
Loose surface crystals study:
The Famotidine encapsulated microcapsules
prepared by different combination of

7. polymers were evaluated by loose surface
crystal study to observe the excess drug
present on the surface of microcapsules. From
each batch, 100 mg of microcapsule was
shaken in 20 ml of 0.1N HCl for 5 min and
then filtered through whatman filter paper 41.
The amount of drug present in filtrate was
determined spectroscopically and calculated
as a percentage of total drug.
Determination of swelling properties:
The dynamic swelling property of
microcapsules in the dissolution medium was
determined. Microcapsules of known weight
were placed in dissolution solution for 6 hr
and the swollen microcapsules were collected
by a centrifuge and the wet weight of the
swollen microcapsules was determined by
first blotting the particles with filter paper to
remove absorbed water on surface and then
weighing immediately on an electronic
balance. The percentage of swelling of
microcapsules in the dissolution media was
115
then calculated by using equation, Sw = [(Wt-
Wo)/Wo] ×100, where, Sw= percentage of
swelling of microcapsules, Wt = weight of the
microcapsules at time t, Wo = initial weight
of the microcapsules. All the experimental
units were studied in triplicate (n=3).
Determination of wall thickness11,12
Wall thickness of microcapsules was
determined by method of Luu et al using
equation, h = [r (1-P) d1/3{Pd2+ (1-P) d1}] ×
100, where, h= wall thickness, r = arithmetic
mean radius of microcapsules, d1 and d2 are

8. densities of core and coat material respectively,
P is the proportion of medicament in
microcapsules. All the experimental units were
studied in triplicate (n=3).
In vitro drug release13
In vitro drug release study was carried out in
USP type-II dissolution test apparatus.
Microcapsules were placed in basket of
dissolution vessel containing 900 ml of 0.1N
HCl maintained at (37±1) °C and stirred at 50
rpm. Aliquots of samples (5 ml) at an interval
of 1 hour were withdrawn and filtered through a
whatman filter paper. The samples were analyzed
for famotidine content by UV-Visible
spectrophotometer at 265 nm .All the experimental
units were analyzed in triplicate (n=3).
In vitro drug release kinetic studies
Kinetic model had described drug
dissolution from solid dosage form where
the dissolved amount of drug is a function
of test time. In order to study the exact
mechanism of drug release from the
microsphere, drug release data was
analyzed according to zero order14, first
order15, Higuchi square root16, Korsmeyer-
Peppas model17. The criteria for selecting
the most appropriate model were chosen on
the basis of goodness of fit test.
Mucoadhesion test by In vitro wash off
method18
A piece of stomach mucosa (5 × 2 cm) was
taken from local slaughter house. It was
mounted on to glass slides with adhesive.
About 100 microcapsules were spread on to
each wet rinsed tissue specimen and

9. immediately thereafter the support was hung
on the arm of a USP tablet disintegrating test
machine. By operating the disintegrating test
machine the tissue specimen was given a
slow regular up and down movement in the
test fluid at 37oC taken in the vessel of the
machine. At the end of every one hour up to
10 hours, the machine was stopped and
number of microcapsules still adhering onto
the tissue was counted.
.
RESULTS AND DISCUSSIONS
The composition of famotidine loaded
mucoadhesive microcapsules using combined
polymers in ratio of 1:3 w/w of drug polymer
was designed and prepared by orifice ionic
gelation method. The obtained microcapsules
were found to be non aggregated. The
generalized microparticulation protocol
depends on, choice of ingredient, successful
preparation of microcapsules and optimization
at every preparative steps. The percentage
yield was found to be in the ranges of 67.7 to
87.5 % and the yield was found satisfactory
in all the formulations as reported in Table 1.
The formulation F3 is showing maximum
yield. The optical microscopy revealed that
all microcapsules thus obtained, were opaque,
discrete and spherical particles with smooth
surfaces further confirmed by SEM study.
The geometric diameter of the microcapsules
lies in the ranges of 380.1 to 723.4 μm as
shown in Table 1. All the formulations having
excellent flow properties as given in Table 1.
The drug entrapment efficiency (DEE) of all

10. the formulations was reported as high profile
ranges from 30.3 to 96.7 % may be due to use
of polymers in combination, as abridged in
Table 1. The maximum DEE was shown by
formulation F3. The shape of famotidine
microcapsule as evidenced from the scanning
electron photomicrograph was spherical and
uniformly distributed shown in Fig 1. The
percentage of moisture loss was found in a
range 2.24 to13.26 % tabularized in Table 2.
The minimum moisture content was observed
with formulation F3. The results ensure the
presence of diminutive water content which
can be due to the involvement of water in
process method and hydrophilic property of
mucoadhesive polymers. But the lessen
proportion of water obtained indicates its
proper drying and instant hardening of
microcapsule due to quick gelation occurred
between calcium chloride and sodium
alginate facilitate the storage behavior of the
formulations. The famotidine loaded
mucoadhesive microcapsules obtained having
circularity factor very close to 1.00, which
confirm their sphericity, as represented in
Table 2. These loose surface crystal studies
lend a hand to estimate the excess amount of
drug attached on the surface of microcapsules
after a successful drug entrapment. The study
was executed with various prepared
formulations and the results were tabularized
in Table 2. The swelling indexes of
microcapsules were found satisfactory and
shown in Table 2, indicates the
hydrophlilicity property of the polymers with

11. establishing the fundamentals that the
increase in swelling index may depends on
the use of polymers in combination in
formulations. The wall thickness was found
to be highest 3.888μm for F2 in comparison
to other formulations as shown in Table 2.
The wall thickness of the microcapsules
mainly built up with polymer content in
formulations. The in vitro famotidine releases
from microcapsules prepared by combination
of polymers were studied. All the formulations
were found to be release famotidine in a
controlled manner for a prolonged period over
9 hours which is represented graphically in Fig
2. Among all the formulations, F3 was found to
release famotidine in a controlled manner with
constant fashion over extended period of time.
To illustrate the kinetic of drug release from
microcapsules, release data was analyzed
according to different kinetic equations
depicted in Table 3. Release data of all
formulations except F1 and F5 following zero
order kinetic showing a constant release profile,
independent of formulation variations. The drug
release of the formulations F1 and F5, have a
diffusion controlled release pattern which is
dependent on concentration of release retarding
polymer as they are best fit in Higuchi square
root kinetic model. The Table 3 showed that all
the formulations release the drug by diffusion
following Fickian (n<0.5) transport mechanism
except the formulation F5, which follow non-
Fickian (n>0.5) transport mechanism. Statistical
verification with one way ANOVA method
attested the fact that the drug release data were

12. found significant at 5 % level of significance (p
< 0.05). The order of mucoadhesion property
among all the formulations was found as
F1>F2>F3>F4>F5, as shown in Fig 3. The
formulations F1, F2 and F3, are showing good
bioadhesion.
.
Fig. 1 : Scanning electron photomicrograph of prepared
microcapsules (f3) under lower
resolution :
CONCLUSION
The formulation F3 containing drug: polymer
ratio 1:3 with polymer combination of
carbopol-934 and SCMC was found to be the
best microcapsule formulation, regarding all
the properties evaluated in order to achieve
objective of this study. The novel formulation
design facilitated the optimization and
successful development of famotidine
microcapsule formulations. Our data
concluded that choice of combination of
polymers instead of single polymer may be an
effective strategy for the designing and
development of famotidine mucoadhesive
microcapsule for easy, reproducible and cost

13. effective method to prove its potential for
safe and effective controlled for oral drug
delivery therapy.
ACKNOWLEDGEMENTS
Authors wish to thank Nicholas Piramol India
limited, for providing gift sample of
Famotidine and also thank Corel Pharma Ltd.,
Ahmadabad, for providing carbopol-934 for
this study.
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